We aim to test the hypothesis that Con A-induced hepatitis and cell death can be prevented by the administration of the MnSOD mimetic MnTBAP. Male C57 mice were divided into 3 groups, 1) pretreated with MnTBAP (30 mg/kg) for 2 days and then Concanavalin A (Con A) (15 mg/kg); 2) pretreated with saline for 2 days and then Con A (15 mg/kg); 3) was the control treated with saline for 3 days. Extensive hepatic necrosis, with a significant increase in apoptosis, lipid peroxidation and decreased MnSOD enzymatic activity was found in the hepatic tissue of Con A-treated mice with significantly attenuation of all factors by pretreatment with MnTBAP. MnTBAP protected hepatocytes from Con A-induced hepatic injury with less degree of liver inflammation—ConA + MnTBAP (2.1 ± 0.4) vs. Con A (2.6 ± 0.3)—and significantly less cell death (1.2 ± 0.3 vs. 2.7 ± 0.4, p = 0.03). MnSOD supplementation attenuated the oxidative-induced stress effects of Con A-induced injury and the protective effects of MnSOD supplementation against Con A-induced hepatitis could be through its anti-oxidative properties. Further evaluation of MnSOD manipulation could have the potential to prevent ongoing hepatic injury in hepatitis.
D. Lavanchy, “Hepatitis B Virus Epidemiology, Disease Burden, Treatment, and Current and Emerging Prevention and Control Measures,” Journal of Viral Hepatitis, Vol. 11, No. 2, 2004, pp. 97-107. doi:10.1046/j.1365-2893.2003.00487.x
W. M. Lee, “Hepatitis B Virus Infection,” The New England Journal of Medicine, Vol. 337, 1997, pp. 1733-1745. doi:10.1056/NEJM199712113372406
A. Wasley and M. J. Alter, “Epidemiology of Hepatitis C: Geographic Differences and Temporal Trends,” Seminars in Liver Disease, Vol. 20, 2000, pp. 1-16. doi:10.1055/s-2000-9506
A. K. Singal and B. S. Anand, “Mechanisms of Synergy between Alcohol and Hepatitis C Virus,” Journal of Clinical Gastroenterology, Vol. 41, No. 8, 2007, pp. 761-772. doi:10.1097/MCG.0b013e3180381584
M. Levrero, “Viral Hepatitis and Liver Cancer: The Case of Hepatitis C,” Oncogene, Vol. 25, 2006, pp. 3834-3847. doi:10.1038/sj.onc.1209562
S. Chitturi and G. C. Farrell, “Etiopathogenesis of Nonalcoholic Steatohepatitis,” Seminars in Liver Disease, Vol. 21, No. 1, 2001, pp. 27-41. doi:10.1055/s-2001-12927
M. Vidali, S. F. Stewart and E. Albano, “Interplay between Oxidative Stress and Immunity in the Progression of Alcohol-Mediated Liver Injury,” Trends in Molecular Medicine, Vol. 14, No. 2, 2008, pp. 63-71. doi:10.1016/j.molmed.2007.12.005
E. Albano, “Alcohol, Oxidative Stress and Free Radical Damage,” Proceedings of the Nutrition Society, Vol. 65, No. 3, 2006, pp. 278-290. doi:10.1079/PNS2006496
J. Choi and J. H. Ou, “Mechanisms of Liver Injury. III. Oxidative Stress in the Pathogenesis of Hepatitis C Virus,” American Journal of Physiology—Gastrointestinal and Liver Physiology, Vol. 290, No. 5, 2006, pp. G847-G851. doi:10.1152/ajpgi.00522.2005
D. Hutter and J. J. Greene, “Influence of the Cellular Redox State on NF-kappaB-Regulated Gene Expression,” Journal of Cellular Physiology, Vol. 183, No. 1, 2000, pp. 45-52. doi:10.1002/(SICI)1097-4652(200004)183:1 3.0.CO;2-P
H. Bartsch and J. Nair, “Accumulation of Lipid Peroxidation-Derived DNA Lesions: Potential Lead Markers for Chemoprevention of Inflammation-Driven Malignancies,” Mutation Research, Vol. 591, No. 1-2, 2005, pp. 34-44. doi:10.1016/j.mrfmmm.2005.04.013
W. E. Stehbens, “Oxidative Stress, Toxic Hepatitis, and Antioxidants with Particular Emphasis on Zinc,” Experimental and Molecular Pathology, Vol. 75, No. 3, 2003, pp. 265-276. doi:10.1016/S0014-4800(03)00097-2
L. W. Oberley, “Mechanism of the Tumor Suppressive Effect of MnSOD Overexpression,” Biomedicine and Pharmacotherapy, Vol. 59, No. 4, 2005, pp. 143-148. doi:10.1016/j.biopha.2005.03.006
R. C. Martin, Q. Liu, J. M. Wo, M. B. Ray and Y. Li, “Chemoprevention of Carcinogenic Progression to Esophageal Adenocarcinoma by the Manganese Superoxide Dismutase Supplementation,” Clinical Cancer Research, Vol. 13, 2007, pp. 5176-5182. doi:10.1158/1078-0432.CCR-07-1152
G. Tiegs, J. Hentschel, and A. Wendel, “A T Cell-Dependent Experimental Liver Injury in Mice Inducible by Concanavalin A,” The Journal of Clinical Investigation, Vol. 90, No. 1, 1992, pp. 196-203. doi:10.1172/JCI115836
H. Mizuhara, M. Uno, N. Seki, M. Yamashita, M. Yamaoka, T. Ogawa, K. Kaneda, T. Fujii, H. Senoh and H. Fujiwara, “Critical Involvement of Interferon Gamma in the Pathogenesis of T-Cell Activation-Associated Hepatitis and Regulatory Mechanisms of Interleukin-6 for the Manifestations of Hepatitis,” Hepatology, Vol. 23, 1996, pp. 1608-1615.
F. Gantner, M. Leist, S. Jilg, P. G. Germann, M. A. Freudenberg and G. Tiegs, “Tumor Necrosis Factor-Induced Hepatic DNA Fragmentation as an Early Marker of T Cell-Dependent Liver Injury in Mice,” Gastroenterology, Vol. 109, 1995, pp. 166-176. doi:10.1016/0016-5085(95)90282-1
F. Gantner, M. Leist, A. W. Lohse, P. G. Germann and G. Tiegs, “Concanavalin A-Induced T-Cell-Mediated Hepatic Injury in Mice: The Role of Tumor Necrosis Factor,” Hepatology, Vol. 21, 1995, pp. 190-198.
R. Bruck, H. Aeed, E. Brazovsky, T. Noor and R. Hershkoviz, “Allicin, the Active Component of Garlic, Prevents Immune-Mediated, Concanavalin A-Induced Hepatic Injury in Mice,” Liver International, Vol. 25, No. 3, 2005, pp. 613-621. doi:10.1111/j.1478-3231.2005.01050.x
H. Shirin, H. Aeed, A. Alin, Z. Matas, M. Kirchner, E. Brazowski, I. Goldiner and R. Bruck, “Inhibition of Immune-Mediated Concanavalin A-Induced Liver Damage by Free-Radical Scavengers,” Digestive Diseases and Sciences, Vol. 55, No. 2, 2009, pp. 268-275. doi:10.1007/s10620-009-0732-5
J. K. Kolls and A. Linden, “Interleukin-17 Family Members and Inflammation,” Immunity, Vol. 21, No. 4, 2004, pp. 467-476. doi:10.1016/j.immuni.2004.08.018
D. V. Jovanovic, J. A. Di Battista, J. Martel-Pelletier, F. C. Jolicoeur, Y. He, M. Zhang, F. Mineau and J. P. Pelletier, “IL-17 Stimulates the Production and Expression of Proinflammatory Cytokines, IL-Beta and TNF- Alpha, by Human Macrophages,” Journal of Immunology, Vol. 160, 1998, pp. 3513-3521.
Z. Yao, W. C. Fanslow, M. F. Seldin, A. M. Rousseau, S. L. Painter, M. R. Comeau, J. I. Cohen and M. K. Spriggs, “Herpesvirus Saimiri Encodes a New Cytokine, IL-17, Which Binds to a Novel Cytokine Receptor,” Immunity, Vol. 3, No. 6, 1995, pp. 811-821. doi:10.1016/1074-7613(95)90070-5
H. Park, Z. Li, X. O. Yang, S. H. Chang, R. Nurieva, Y. H. Wang, Y. Wang, L. Hood, Z. Zhu, Q. Tian and C. Dong, “A Distinct Lineage of CD4 T Cells Regulates Tissue Inflammation by Producing Interleukin 17,” Nature Immunology, Vol. 6, 2005, pp. 1133-1141. doi:10.1038/ni1261
J. Schumann, D. Wolf, A. Pahl, K. Brune, T. Papadopoulos, N. van Rooijen and G. Tiegs, “Importance of Kupffer Cells for T-Cell-Dependent Liver Injury in Mice,” American Journal of Pathology, Vol. 157, No. 5, 2000, pp. 1671-1683. doi:10.1016/S0002-9440(10)64804-3
C. S. Bonder, M. N. Ajuebor, L. D. Zbytnuik, P. Kubes and M. G. Swain, “Essential Role for Neutrophil Recruitment to the Liver in Concanavalin A-Induced Hepatitis,” Journal of Immunology, Vol. 172, 2004, pp. 45-53.
K. Takeda, Y. Hayakawa, L. Van Kaer, H. Matsuda, H. Yagita and K. Okumura, “Critical Contribution of Liver Natural Killer T Cells to a Murine Model of Hepatitis,” Proceedings of the National Academy of Sciences of the United States of America, Vol. 97, No. 10, 2000, pp. 5498-5503. doi:10.1073/pnas.040566697
G. Tiegs, “T cells, NKT Cells, and NK Cells in an Experimental Model of Autoimmune Hepatitis,” In: M. E. Gershwin, J. M. Vierling and M. P. Manns, Eds., Liver Immunology, Hanley & Belfus Inc; Philadelphia, 2003, pp. 171-183.
G. Beldi, Y. Wu, Y. Banz, M. Nowak, L. Miller, K. Enjyoji, A. Haschemi, G. G. Yegutkin, D. Candinas, M. Exley and S. C. Robson, “Natural Killer T Cell Dysfunction in CD39-Null Mice Protects against Concanavalin A-Induced Hepatitis,” Hepatology, Vol. 48, No. 3, 2008, pp. 841-852. doi:10.1002/hep.22401
T. Kawamura, K. Takeda, H. Kaneda, H. Matsumoto, Y. Hayakawa, D. H. Raulet, Y. Ikarashi, M. Kronenberg, H. Yagita, K. Kinoshita, T. Abo, K. Okumura and M. J. Smyth, “NKG2A Inhibits Invariant NKT Cell Activation in Hepatic Injury,” Journal of Immunology, Vol. 182, No. 1, 2009, pp. 250-258.
W. Jiang, R. Sun, R. Zhou, H. Wei and Z. Tian, “TLR-9 Activation Aggravates Concanavalin A-Induced Hepatitis via Promoting Accumulation and Activation of Liver CD4+ NKT Cells,” Journal of Immunology, Vol. 182, No. 6, 2009, pp. 3768-3774. doi:10.4049/jimmunol.0800973
T. Nagata, L. McKinley, J. J. Peschon, J. F. Alcorn, S. J. Aujla and J. K. Kolls, “Requirement of IL-17RA in Con A Induced Hepatitis and Negative Regulation of IL-17 Production in Mouse T Cells,” Journal of Immunology, Vol. 181, No. 11, 2008, pp. 7473-7479.
H. Nakashima, M. Kinoshita, M. Nakashima, Y. Habu, S. Shono, T. Uchida, N. Shinomiya and S. Seki, “Superoxide Produced by Kupffer Cells Is an Essential Effector in Concanavalin A-Induced Hepatitis in Mice,” Hepatology, Vol. 48, No. 6, 2008, pp. 1979-1988. doi:10.1002/hep.22561
H. Ohshima, M. Tatemichi and T. Sawa, “Chemical Basis of Inflammation-Induced Carcinogenesis,” Archives of Biochemistry and Biophysics, Vol. 417, No. 1, 2003, pp. 3-11. doi:10.1016/S0003-9861(03)00283-2
M. Karin and F. R. Greten, “NF-kappaB: Linking Infla- mmation and Immunity to Cancer Development and Progression,” Nature Reviews Immunology, Vol. 5, 2005, pp. 749-759. doi:10.1038/nri1703
H. Kamata, S. Honda, S. Maeda, L. Chang, H. Hirata and M. Karin, “Reactive Oxygen Species Promote TNFalpha-Induced Death and Sustained JNK Activation by Inhibiting MAP Kinase Phosphatases,” Cell, Vol. 120, No. 5, 2005, pp. 649-661. doi:10.1016/j.cell.2004.12.041
S. Kawanishi, Y. Hiraku, S. Pinlaor and N. Ma, “Oxidative and Nitrative DNA Damage in Animals and Patients with Inflammatory Diseases in Relation to Inflammation-Related Carcinogenesis,” The Journal of Biological Chemistry, Vol. 387, No. 4, 2006, pp. 365-372. doi:10.1515/BC.2006.049
K. Koike, “Molecular Basis of Hepatitis C Virus-Associated Hepatocarcinogenesis: Lessons from Animal Model Studies,” Clinical Gastroenterology and Hepatology, Vol. 3, No. 2, 2005, pp. S132-S135. doi:10.1016/S1542-3565(05)00700-7
X. W. Wang, S. P. Hussain, T. I. Huo, C. G. Wu, M. Forgues, L. J. Hofseth, C. Brechot and C. C. Harris, “Molecular Pathogenesis of Human Hepatocellular Carcinoma,” Toxicology, Vols. 181-182, 2002, pp. 43-47. doi:10.1016/S0300-483X(02)00253-6
R. C. Martin, Q. Liu, J. M. Wo, M. B. Ray and Y. Li, “Chemoprevention of Carcinogenic Progression to Esophageal Adenocarcinoma by the Manganese Superoxide Dismutase Supplementation,” Clinical Cancer Research, Vol. 13, 2007, pp. 5176-5182. doi:10.1158/1078-0432.CCR-07-1152
M. Patel and B. J. Day, “Metalloporphyrin Class of Therapeutic Catalytic Antioxidants,” Trends in Pharmacological Sciences, Vol. 20, No. 9, 1999, pp. 359-364. doi:10.1016/S0165-6147(99)01336-X
S. Cuzzocrea, B. Zingarelli, G. Costantino and A. P. Caputi, “Beneficial Effects of Mn(III)Tetrakis (4-benzoic acid) Porphyrin (MnTBAP), a Superoxide Dismutase Mimetic, in Carrageenan-Induced Pleurisy,” Free Radical Biology & Medicine, Vol. 26, No. 1-2, 1999, pp. 25-33. doi:10.1016/S0891-5849(98)00142-7
A. G. Estevez, N. Spear, S. M. Manuel, R. Radi, C. E. Henderson, L. Barbeito and J. S. Beckman, “Nitric Oxide and Superoxide Contribute to Motor Neuron Apoptosis Induced by Trophic Factor Deprivation,” The Journal of Neuroscience, Vol. 18, No. 3, 1998, pp. 923-931.
B. J. Day, I. Fridovich and J. D. Crapo, “Manganic Porphyrins Possess Catalase Activity and Protect Endothelial Cells against Hydrogen Peroxide-Mediated Injury,” Archives of Biochemistry and Biophysics, Vol. 347, No. 2, 1997, pp. 256-262. doi:10.1006/abbi.1997.0341